HuD and the Survival Motor Neuron protein interact in motoneurons and are essential for motoneuron development, function and mRNA regulation

Hao, L.T., Duy, P.Q., An, M., Talbot, J., Iyer, C.C., Wolman, M., Beattie, C.E.
The Journal of neuroscience : the official journal of the Society for Neuroscience   37(48): 11559-11571 (Journal)
Registered Authors
An, Min, Beattie, Christine, Talbot, Jared, Wolman, Marc
MeSH Terms
  • Animals
  • Animals, Genetically Modified
  • Axons/physiology
  • Dendrites/genetics
  • Dendrites/metabolism
  • ELAV-Like Protein 4/genetics*
  • ELAV-Like Protein 4/metabolism*
  • Motor Neurons/physiology*
  • Muscular Atrophy, Spinal/genetics
  • Muscular Atrophy, Spinal/metabolism
  • RNA, Messenger/physiology*
  • Survival of Motor Neuron 1 Protein/genetics*
  • Survival of Motor Neuron 1 Protein/metabolism*
  • Zebrafish
29061699 Full text @ J. Neurosci.
Motoneurons establish a critical link between the CNS and muscles. If motoneurons do not develop correctly, they cannot form the required connections, resulting in movement defects or paralysis. Compromised development can also lead to degeneration because the motoneuron is not set up to function properly. Little is known, however, regarding the mechanisms that control vertebrate motoneuron development, particularly the later stages of axon branch and dendrite formation. The motoneuron disease spinal muscular atrophy (SMA) is caused by low levels of the survival motor neuron (SMN) protein leading to defects in vertebrate motoneuron development and synapse formation. Here we show using zebrafish as a model system that SMN interacts with the RNA binding protein (RBP) HuD in motoneurons in vivo during formation of axonal branches and dendrites. To determine the function of HuD in motoneurons, we generated zebrafish HuD mutants and found that they exhibited decreased motor axon branches, dramatically fewer dendrites, and movement defects. These same phenotypes are present in animals expressing low levels of SMN, indicating that both proteins function in motoneuron development. HuD binds and transports mRNAs and one of its target mRNAs, Gap43, is involved in axonal outgrowth. We found that Gap43 was decreased in both HuD and SMN mutants. Importantly, transgenic expression of HuD in motoneurons of SMN mutants rescued the motoneuron defects, the movement defects, and Gap43 mRNA levels. These data support that the interaction between SMN and HuD is critical for motoneuron development and point to a role for RBPs in SMA.SIGNIFICANCE STATEMENT In zebrafish models of the motoneuron disease spinal muscular atrophy (SMA), motor axons fail to form the normal extent of axonal branches and dendrites leading to decreased motor function. SMA is caused by low levels of the survival motor neuron (SMN) protein. We show in motoneurons in vivo that SMN interacts with the RNA binding protein, HuD. Novel mutants reveal that HuD is also necessary for motor axonal branch and dendrite formation. Data also revealed that both SMN and HuD affect levels of an mRNA involved in axonal growth. Moreover, expressing HuD in SMN-deficient motoneurons can rescue the motoneuron development and motor defects caused by low levels of SMN. These data support that SMN:HuD complexes are essential for normal motoneuron development and indicate that mRNA handling is a critical component of SMA.
Genes / Markers
Mutation and Transgenics
Human Disease / Model Data
Sequence Targeting Reagents
Engineered Foreign Genes
Errata and Notes